EP0757055B1 - Glycosides, produits de dégradation exempt de sucre, et dérivés de tels produits - Google Patents

Glycosides, produits de dégradation exempt de sucre, et dérivés de tels produits Download PDF

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EP0757055B1
EP0757055B1 EP96110132A EP96110132A EP0757055B1 EP 0757055 B1 EP0757055 B1 EP 0757055B1 EP 96110132 A EP96110132 A EP 96110132A EP 96110132 A EP96110132 A EP 96110132A EP 0757055 B1 EP0757055 B1 EP 0757055B1
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Prior art keywords
formula
residue
group
residues
hexose
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English (en)
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EP0757055A2 (fr
EP0757055A3 (fr
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Jean-Claude Jaton
Fabrizio Marazza
Ari Lewenstein
Francis M. Sirotnak
Bernhard Jaun
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Cerbios Pharma SA
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Cerbios Pharma SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C62/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C62/30—Unsaturated compounds
    • C07C62/32—Unsaturated compounds containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C62/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C62/30—Unsaturated compounds
    • C07C62/34—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C69/757—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety

Definitions

  • the present invention relates to new glycosides that come from the aqueous extract of Plant pollen were isolated and also new aglycones, that after the separation of sugar constituents from them Glycosides have been obtained and new derivatives Aglycones.
  • the new connections mentioned can, for example, as active ingredients in pharmaceutical Preparations are used.
  • Plant pollen has been known for a long time, and it is said to be in this connection, for example, to the German patent specification No. 1,467,750 and the Austrian patent specification No. 255 634, in which procedures for Production of such pollen extracts are described that of the high-molecular proteins of the pollen shell in the are essentially exempt, which may be allergies can cause.
  • the corresponding, with watery Extraction agents, or with non-aqueous extraction agents obtained pollen extracts and also mixtures they have been commercially available for many years, and they are used as a tonic to increase the Defenses, for the treatment of prostate ailments, for acceleration healing wounds and broken bones and used as an anti-inflammatory agent.
  • the pollen extracts described there, or the active ingredient fractions isolated from the pollen extracts therefore have a cytostatic activity, i.e. the growth of various cancer cells, such as Leukemia cells and human prostate cancer cells, larynx cancer cells, Liver cancer cells, bladder cancer cells and Breast cancer cells could be found in appropriate cell cultures be strongly inhibited.
  • various cancer cells such as Leukemia cells and human prostate cancer cells, larynx cancer cells, Liver cancer cells, bladder cancer cells and Breast cancer cells could be found in appropriate cell cultures be strongly inhibited.
  • the new active ingredient fractions or the ones from them isolated active ingredients, or synthetically produced corresponding new drug derivatives, namely the Property to increase the immune response of warm-blooded animals modulate.
  • New glycosides have now been isolated from the aqueous extract of plant pollen, which have the following formula I exhibit.
  • R is a hydrogen atom or a further sugar residue, in particular glucose residue, which is glycosidically bound to the glucose shown here in the 6-position thereof.
  • the residue of an unsubstituted 2-oxindole-3-acetic acid of the formula A is thus in the glycosides of the structural formula I given above bound via its carboxyl group to the hydroxyl group in the 6-position of a molecule of glucose in the manner of an ester.
  • This glucose molecule is in turn bound to the phenolic hydroxyl group in the 6-position of the indane skeleton of an aglycone, which has the following formula II having.
  • a phenyl nucleus is bonded in the 1-position of the indane skeleton, which is substituted in the p-position by a hydroxyl group and in the m-position by a methoxy group.
  • the carboxyl groups bonded to positions 2 and 3 are in the cis position to one another, while the phenyl nucleus bonded to the 1 position of the indane skeleton is trans to the carboxyl group which is connected to the 2nd -Position of the indane scaffold is bound.
  • glycosides of formula I in which R represents a hydrogen atom is also the ⁇ -fructose glycosidically bound a residue of the ⁇ -glucose, so that the two carboxyl groups of the compounds structure bound by formula II from two hexose units corresponds to that of sucrose.
  • this hexose residue is preferably the Remaining another glucose unit.
  • Another object of the present invention is a method for isolating fractions containing glycosides from the pollen extract obtained with aqueous extractants, and this method is characterized in that the pollen extract, which may also contain maltodextrins as further constituents, is dissolved in water and subjecting to dialysis with a membrane which retains substances of a molecular weight of more than 1000 daltons, the material diffusing through the membrane being discarded and in a second dialysis step, the material that did not diffuse through the membrane is subjected to dialysis using a membrane that retains materials with a molecular weight above 3500 Daltons, preferably a membrane that retains materials with a molecular weight above 2000 Daltons, and then that dialysate passing through this membrane is evaporated under vacuum and fractions containing the glycosides of the formula I are isolated therefrom by gel filtration.
  • the pollen extract which may also contain maltodextrins as further constituents
  • this isolation process becomes the yellowish-white powder Pollen extract initially about 3-4 times Amount of distilled water dissolved and this solution under Use of membranes containing substances with a Retain molecular weight above 1000 daltons, against Dialyzed water in the cold.
  • the inner solution that is, the material that did not pass through the membrane is, generally focused on one Volume that is about half the volume of the aqueous Solution that has been subjected to this dialysis.
  • This concentrated solution of the membrane retained product is brown in color, and evaporation to dryness shows that the Yield 12 to 25%, based on the yellowish white Powder used as a raw material is.
  • a second dialysis step the product of the first dialysis step obtained after lyophilization dissolved in 2-5 times the amount of water, and the aqueous solution is made using a membrane, the products with a molecular weight of over 2000 daltons does not pass, dialyzed against water. Dialysis takes place during a week, about 20 times Volume of water is used as an external solution and this external solution is changed daily.
  • the outside solutions are combined and concentrated and then under vacuum to Evaporated dry.
  • the yield is 10-30%, based to that subject to this second dialysis step solid raw material.
  • the product obtained in this second dialysis is referred to as A2.
  • Fraction IIIb is replaced by another similar gel filtration in five fractions divided, of which fraction III-b5 is the one those in the pharmacological tests carried out shows highest activity.
  • This fraction III-b5 is by high pressure liquid chromatography further cleaned, two Major fractions isolated with III-b51 and III-b52, or abbreviated as b51 or b52.
  • both the glycoside b51 and the glycoside b52 is such a compound of formula I, in which the rest R stands for hydrogen.
  • this glycoside of formula I is a has a large number of chiral centers, namely for example the carbon atoms in positions 2, 10 and 9 of the Indan scaffold, so is the difference between the glycoside b51 and the glycoside b52, only due to a different configuration on the chiral Center of indolylacetic acid.
  • Appropriate Studies have shown that the glycoside b51 of the glycoside b52 in terms of configuration at the chiral Center of the carbon atom in the 3-position of the 2-oxindole-3-acetic acid differs.
  • the 2-oxindole-3-acetic acid of formula A such as also the 2-oxo-1,2,3,4-tetrahydroquinoline-4-carboxylic acid have long been known in the form of their racemate.
  • indane derivative of the formula II a new chemical compound was mentioned.
  • the indane derivative of the formula II has a molecular weight from 360 daltons. This dicarboxylic acid cleaves due to the cis position of the two carboxyl groups water very easily, so in the mass spectrum, depending on the recording conditions, practically only one Anhydride corresponding mass peak was observed has a molecular weight that is 18 daltons lower, so a molecular weight of 342 daltons.
  • fraction IIIa isolate two main peaks by column chromatography, which are referred to as A3 and A4. Of these results the peak A3 in high pressure liquid chromatography three major fractions, designated A31, A32 and A34 become.
  • A4 Leave out of the second peak labeled A4 two fractions by high pressure liquid chromatography Isolate those designated as A41 and A42. Each of these two fractions has a molecular weight from 1163 Dalton and it turned out that in one aqueous solution again a balance between A41 and A42 exists.
  • the acid hydrolysis results in the pair A41 / A42, among other things, an aglycon that matches the one Aglycon are identical, which is characterized by the acid hydrolysis the pair b51 / b52 is obtained.
  • the glycoside A41 differs from the glycoside A42 only in terms of configuration on that chiral Center, which is represented by the carbon atom in the 3-position of the heterocyclic ring of the rest of the 2-oxindole-3-acetic acid is formed.
  • This glycoside can be treated further residues of glucose are still split off, for example a radical R in the meaning of an ⁇ -glucosidic bound glucose residues by treatment with ⁇ -glucosidase be split off, so that you have appropriate Receives products of the above formula in which R stands for hydrogen.
  • Another object of the present invention are pharmaceutical preparations for modulation of the immune system in warm-blooded animals are characterized as an active ingredient a glycoside of the formulas I or IV or a given above Aglycon of Formula II or a given above Derivative of the aglycone of the formula given above III included.
  • the new glycosides of formulas I and IV, as well the Algycon of the formula II and their derivatives of the formula IV, can be used as active ingredients in such pharmaceutical Preparations are used, through which tumors, various Viral diseases, especially those that caused by retroviruses, such as AIDS, and other pathological conditions are treated which can lead to a weakening of the immune system or associated with a reduced immune response.
  • aqueous pollen extract was prepared from the pollen from plants, for example rye, by extraction with a mixture of water and a completely water-soluble organic solvent, for example acetone.
  • the pollen was stirred at a temperature of 30-32 o C for 48 hours.
  • the high-molecular proteins and sugars of the pollen are broken down by auto-fermentation.
  • the mixture was then stirred at 30 o for a further 20 to 30 hours.
  • the aqueous medium was from the pollen filtered off, and the clear solution thus obtained under Vacuum evaporated to dryness. You got the dried plant pollen extract in the form of a yellowish-white powder.
  • the length of the tube was about 45 cm, and about a third of its total volume was filled with this solution.
  • Six such tubes were produced and placed in 10 l of cold water and the dialysis was carried out in the cold (about 4 ° C.) for 24 hours. After this time, the external solution was removed and discarded and exchanged for 10 l of cold water. After a further dialysis time of 48 hours, the material remaining in the tubes was removed and the contents of each of the six tubes were evaporated to dryness under vacuum.
  • This second dialysis step was under Using a membrane performed the substances with a molecular weight of 2000 daltons.
  • the product of the second dialysis step was gel filtration using Sephadex G-25 Subject to SF. A column of one was used for this Diameter of 3.6 cm and a length of 90 cm. As Deionized water was used, and the The flow rate of the eluent was 20 ml / hour. There were Fractions of 10 ml collected.
  • Fraction IIIb was subjected to further gel filtration using one with Sephadex G-25 SF filled column, and this second gel filtration 5 fractions were won, of which the Fraction III-b4 was slightly yellowish and fraction b5 Contained 80% of the total solid by evaporation each of the five fractions were kept dry.
  • Fraction III-b5 was subjected to high pressure liquid chromatography subjected to two main fractions received, which were designated b51 and b52. These fractions showed absorption in the UV range at 280 mn and they contained 40% of the Solids by high pressure liquid chromatography had been subjected.
  • Example 1 The procedure according to Example 1 was followed worked, again using the first dialysis a membrane was carried out, the substances with a molecular weight of at least 1000 daltons. In this case, 115 g of the yellowish-white Powder dissolved in 500 ml of water and dialysis was started against a volume of 10 l of water. The Dialysis was carried out in the cold for 48 hours, the external solution changed and discarded four times has been.
  • the combined inner solutions were lyophilized and 16 g of dry product were obtained. Accordingly was the yield based on that of Solid subjected to dialysis 14% by weight.
  • the second dialysis step was in this Case performed using a spectral membrane, the materials with a molecular weight of 3500 Restrained Dalton and more.
  • 16 g of the product of the first dialysis step were dissolved in 40 ml of water and against 1 l of water dialyzed for 24 hours. Then the outside solution removed and saved, and it was kept during further Dialyzed against 1 liter of fresh water for 24 hours.
  • Fraction III-b was made using a column filled with Sephadex G-25 SF in five active ingredient fractions divided that with III-b1, b2, b3, b4 and b5. It turned out that the faction b5 80% of the solids of all fractions b1 to contained b5.
  • This fraction III-b5 was by high pressure liquid chromatography further cleaned, taking two fractions were obtained that have a light absorption in the UV range at 280 nm. These two factions are designated b51 and b52.
  • the pure fraction b51 in water gradually mix from b51 and b52, and that on the other hand the pure Fraction b52 in water also a mixture of b51 and b52 forms with the same mixing ratio.
  • the Equilibrium in the aqueous solution is around 40 Wt% b52 and 60 wt% b51. From the equilibrium mixture can be again by column chromatography Isolate fraction b51 and a fraction b52.
  • Example 1 gel filtration on the Sephadex G-25 Pillar three fractions labeled IIIa, IIIb and IIIc isolated.
  • the faction is now IIIa another separation using one with Subjected to Sephadex G-25 filled column.
  • this pillar 140 mg of fraction IIIa were applied and at this gel filtration gave a fraction with the Designation A3, which after evaporation 30 mg of solid delivered and a fraction called A4, the after evaporation to dryness provided 66 mg.
  • the total amount in the A3 and A4 was included, corresponding to a yield of 65% of the applied solid.
  • Fraction A3 was subjected to high pressure liquid chromatography and subjected to two main fractions won with the designation A41 and A42.
  • the A41 / A42 pair of glycosides are also changing the glycosides of this pair are interlinked in aqueous solution um, whereby here too, regardless of whether one of the Glycoside A41 or starting from Glycosid A42, some time sets an identical equilibrium mixture 1. Also in this case there is a difference between the glycoside A41 and the glycoside A42 in the steric configuration at the chiral center in the 3-position of the indole nucleus 2-oxindole-3-acetic acid.
  • glycosides b51 / b52 isolated according to Example 2 was treated under mild alkaline conditions.
  • a glycoside of the following structure was found be isolated, in which glycoside R was a hydrogen atom and Z was also a hydrogen.
  • mice that were 5-7 weeks old were used and weighed 19-22 g.
  • group 1 the animals were not subjected to any further treatment.
  • the animals in groups 2-6 were then followed by intraperitoneal injection administered the glycoside of the formula I, in which R was a hydrogen atom.
  • This Glycoside was on day 1 in a dosage of 50 ug per Mouse (group 2), or 75 ⁇ g per mouse (group 3), or 100 ⁇ g per mouse (group 4) or 150 ⁇ g per mouse (group 5), or 200 ⁇ g per mouse (group 6) administered.
  • the injections were in the same dose on days 3, 5, 7 and 9 repeated.
  • test results were at different similar to other human tumor cells like this is described above for the tumor S-180 cells. Also in this case could be done quickly with the glycoside of formula I. healing of the tumors can be achieved.
  • glycoside was also used in cell cultures examined for its tumor activity. It showed it turns out that this glycoside has no cytotoxic properties exerted on the tumor cells.
  • Example 8 Analog tests as described in Example 8 were carried out with the glycoside of the formula I, in which R is another glycosidically bound glucose residue is. In this case, the test results were those very similar to Example 8. Here too is itself at the lowest dosage of only 50 ⁇ m per mouse / injection in the first test group one in 30% of the animals complete healing has been noted.

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Claims (13)

  1. Glucosides activité pharmacologique, caractérisés en ce qu'ils présentent la formule suivante
    Figure 00440001
       dans laquelle
    R représente un atome d'hydrogène ou un reste hexose à liaison glucosidique ou un groupe de 2 ou plus de deux restes hexose et
    Z représente un groupe de la formule A
    Figure 00440002
    ou de la formule B
    Figure 00450001
    ou en ce que ces glucosides présentent la formule suivante
    Figure 00450002
    où, dans ces glucosides,
    Z1 représente un reste glucosidique de la formule A ci-avant ou de la formule B ci-avant.
  2. Glucoside selon la revendication 1, caractérisé en ce qu'il présente la formule I suivante
    Figure 00450003
       dans laquelle
    R représente un atome d'hydrogène ou un reste hexose, de préférence un reste glucose.
  3. Dérivés d'indane à activité pharmacologique, caractérisés en ce qu'il présentent la formule III suivante
    Figure 00460001
       dans laquelle
    R1 et R2 représentent indépendamment l'un de l'autre des groupes de formule -O-X, dans laquelle
    X représente l'hydrogène, des radicaux alkyles substitués ou non substitué, comportant de 1 à 6 atomes de carbone, par exemple des radicaux aralkyle, ou des radicaux aryle substitués ou non substitués, ou un ou plusieurs restes hexose à liaison ester, ou bien
    R1 et R2 représentent ensemble un groupement bivalent de formule -O- ou -O-Y-O-
       dans laquelle
    Y représente un reste organique bivalent, en particulier un reste hydrocarbure aliphatique, cycloaliphatique ou aromatique, et
    R3, R4, R5 et R6 représentent indépendamment les uns des autres un atome d'hydrogène, un radical alkyle éventuellement substitué, un radical cycloalkyle éventuellement substitué, un radical aryle éventuellement substitué ou des restes acyle d'acides carboxyliques aliphatiques, cycloaliphatiques ou aromatiques, ou un ou plusieurs restes hexose.
  4. Dérivés d'indane selon la revendication 3, caractérisés en ce que, dans ces dérivés,
    R1 et R2 représentent un radical hydroxy,
    R3, R4 et R5 représentent un atome d'hydrogène et R4 représente un radical méthyle.
  5. Dérivés d'indane selon la revendication 3 ou 4, caractérisés en ce qu'ils présentent la configuration relative illustrée par la formule Illa suivante
    Figure 00470001
       dans laquelle
    R1, R2, R3, R4, R5 et R6 ont les mêmes significations que dans la formule IIIa.
  6. Dérivés d'indane selon la revendication 5, caractérisés en ce qu'ils présentent la configuration relative illustrée par la formule IIa suivante
    Figure 00480001
  7. Préparation pharmaceutique pour la modulation du système immunitaire d'animaux à sang chaud, caractérisée en ce qu'elle contient en tant qu'agent actif un glucoside de la formule structurelle indiquée à la revendication 1 ou un dérivé d'indane de la formule III selon la revendication 3.
  8. Préparation pharmaceutique selon la revendication 7, caractérisée en ce qu'elle contient en tant qu'agent actif un glucoside selon la revendication 2 ou un dérivé d'indane selon l'une des revendications 4 à 6.
  9. Préparation pharmaceutique selon la revendication 7 ou 8, caractérisée en ce qu'elle consiste en une préparation destinée à combattre des tumeurs in vivo ou à combattre des maladies virales, en particulier des maladies provoquées par des rétrovirus, par exemple le SIDA, et qu'elle contient les agents actifs des formules indiquées ou des sels pharmaceutiquement acceptables de ces agents actifs.
  10. Procédé d'obtention des glucosides selon la revendication 1, caractérisé en ce que l'on obtient à partir de l'extrait aqueux de pollens végétaux des glucosides de la formule suivante,
    Figure 00490001
    dans laquelle
    R représente un atome d'hydrogène ou un reste hexose à liaison glucosidique et
    Z représente le reste glucosidique, lié via l'unité de β-glucose, de la formule A
    Figure 00490002
       en que l'on retient de l'extrait aqueux du pollen végétal, par dialyse sur membrane, les substances d'un poids moléculaire supérieur à 1000 Dalton, que l'on élimine les composants qui traversent la membrane et qu'ensuite, dans une deuxième étape de dialyse sur membrane, on retient les matières d'un poids moléculaire supérieur à 3500 Dalton, de préférence supérieur à 2000 Dalton, en isolant les glucosides du dialysat traversant la membrane par chromatographie en phase liquide sous haute pression,
       et que l'on traite éventuellement les produits ainsi obtenus dans des conditions légèrement basiques, obtenant ainsi les glucosides de la formule indiquée ci-dessus, dans laquelle Z représente l'unité de β-glucose de la formule B, ou bien
       que l'on soumet le glucoside de la formule indiquée, dans lequel Z représente le groupe de la formule A ci-avant, à une fission estérique, isolant le glucoside respectif de la formule
    Figure 00500001
       dans
    laquelle Z1 représente un groupe glucosidique de la formule A ou le reste glucose de la formule B.
  11. Procédé de préparation de l'aglucone de la formule III selon la revendication 3,
       dans laquelle
    R1 et R2 représentent des radicaux hydroxy,
    R3, R5 et R6 représentent l'hydrogène et
    R4 représente un radical méthyle,
       caractérisé en ce que l'on soumet le glucoside préparé par le procédé selon la revendication 10 à une fission hydrolytique acide et que l'on isole l'aglucone de la formule III.
  12. Procédé selon la revendication 11, caractérisé en ce que l'on isole, à partir du produit de la fission hydrolytique, un aglucone de la formule IIa selon la revendication 6.
  13. Procédé selon la revendication 11 ou 12, caractérisé en ce que l'on synthétise à partir de l'aglucone de la formule III, et/ou IIa, le composé de la formule III selon la revendication 3, et/ou de la formule IIIa selon la revendication 5, par des réactions d'éthérification, des réactions d'estérification ou fission éthérique, et que dans ledit composé au moins un des substituants R1 et R2 possède une signification autre que celle d'un radical hydroxy, ou bien au moins un des radicaux R3, R5 ou R6 possède une signification autre que celle d'un atome d'hydrogène ou que le radical R4 possède une signification autre que celle d'un radical méthyle.
EP96110132A 1995-06-30 1996-06-23 Glycosides, produits de dégradation exempt de sucre, et dérivés de tels produits Expired - Lifetime EP0757055B1 (fr)

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CH193095 1995-06-30
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EP0757055A3 EP0757055A3 (fr) 1998-04-22
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AU2002224372A1 (en) * 2000-10-11 2002-04-22 Avlan Limited Aryl-indane compounds for use as inhibitors of p-glycoprotein mediated transport
WO2006136871A1 (fr) * 2005-06-21 2006-12-28 Codex V S.R.L. Utilisation d'extraits de pollen pour traiter des infections, des neoplasmes et pour equilibrer la reponse immunitaire
JP5924634B2 (ja) 2007-06-21 2016-05-25 株式会社Ｊ−オイルミルズ 配糖体アグリコンの製造方法
FR3055215B1 (fr) * 2016-08-31 2020-02-14 S.A.M. Serelys Pharma Composition comprenant des extraits de pollen et /ou de pistils
GB201712380D0 (en) 2017-08-01 2017-09-13 British American Tobacco Investments Ltd A modular tobacco industry product

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US4644072A (en) * 1985-04-12 1987-02-17 Bristol-Myers Company Intermediates for the production of epipodophyllotoxin and related compounds and processes for the preparation and use thereof
EP0220453B1 (fr) * 1985-09-20 1992-04-15 Cernitin S.A. Application d'extraits de pollen de plantes à la préparation de compositions pharmaceutiques ralentissant la croissance de cellules tumorales et procédé pour leur préparation
RU2125980C1 (ru) * 1991-11-05 1999-02-10 Смитклайн Бичам Корпорейшн Антагонисты эндотелиновых рецепторов, фармкомпозиция, способ их получения, способ подавления эндотелиновых рецепторов

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JPH09104693A (ja) 1997-04-22
US5712377A (en) 1998-01-27
EP0757055A2 (fr) 1997-02-05
ATE186054T1 (de) 1999-11-15
DE59603464D1 (de) 1999-12-02
EP0757055A3 (fr) 1998-04-22

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